Compositions and methods for enhanced pharmacological activity of compositions comprising peptide drug substances

ABSTRACT

Pharmaceutical agents, compositions containing the same and methods for their use for enhancing the bioavailability and pharmacological efficacy of therapeutic peptides. The pharmaceutical agents have the formula 
     Carrier-Linker-Peptide 
     Wherein Peptide is a therapeutically active peptide species having the formula aa n  wherein n is the number of amino acid residues in the peptide and n is 2 to 40, Carrier is benzoyl, phenylacetyl, cinnamoyl, 3-OH-cinnamoyl, 3,4-OH-cinnamoyl, 3,4-dimethoxycinnamoyl, 3,4-methylenedioxycinnamoyl, 3-methoxycinnamoyl, 3,4-diethoxy-cinnamoyl, 3,4,5-trimethoxy-cinnamoyl, t-butoxycarbonyl, benzyloxycarbonyl, pivaloyl, N-9-fluorenylmethoxycarbonyl, fumaroyl and derivatives thereof and Linker is a C6 to C16 lipidic chain or a derivative thereof, an 8-amino-3,6-dioxaoctanoic acid or polymeric derivative thereof, pseudo peptide, or peptide mimic. Methods of use of compositions having the formula Carrier-Peptide wherein Carrier and Peptide are as just defined are also disclosed.

REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-consolidation of applicationsSer. No. 09/844,426 filed Aug. 7, 2000; Ser. No. 10/050,903 filed Jan.16, 2002; and Ser. No. 10/237,254 filed Sep. 6, 2002. This applicationclaims benefit under Title 35, U.S.C. § 119(e), of U.S. applicationsSer. Nos. 60/147,749 filed Aug. 6, 1999; 60/317,737, filed Sep. 6, 2001;60/262,337, filed Jan. 17, 2001; 60/332,636, filed Nov. 6, 2001;60/287,872, filed May 1, 2001; and 60/287,886, filed May 1, 2001.

FIELD OF THE INVENTION

[0002] This invention, in general, relates to compositions and methodsthat permit oral and parenteral administration, and significantlyenhance the bioavailability and pharmacological effects oftherapeutically active peptides, pseudo-peptides and peptide mimics,particularly those that are otherwise poorly orally absorbable ordisplay only minimal bioavailability if administered parenterally.

BACKGROUND OF THE INVENTION

[0003] It has been reported in the literature that therapeuticallyeffective peptides (aa_(n)) with two or more amino acids (n≧2) arepoorly absorbed orally. Even a peptide of as few as two amino acids, orrelated structures, exhibits very narrow absorption windows and poorbioavailability. As an example, the Physician's Desk Reference (PDR)reports that the angiotensin converting enzyme (ACE) inhibitorEnalaprilat (R₁-Ala-Pro; n=2) is very poorly absorbed orally. Enalapril(R₂-Ala-Pro), which is a pro-drug of Enalaprilat, is better absorbedorally, but the end result demonstrates only a 25% relativebioavailability of the active moiety (Enalaprilat) released from in vivocleavage of the pro-drug. In comparison, Lisinopril (R₃-Lys-Pro) hasrelatively good solubility in water, but only a moderate oralbioavailability (<25%), with a T_(max) (time to maximum serum levels invivo) of more than seven hours. Thus, this class of therapeutic speciesis preferably administered via a non-oral delivery method, such as byinjection. However, even when delivered intravenously, thetherapeutically active species has a relatively short serum half-life.

[0004] It is also known that some tri-peptides originating in foodproducts may be capable of effective oral absorption, but to an unknownextent. However, no active tri- or longer peptide drug substances (n≧3)displaying oral absorption have been identified.

[0005] In accordance with the present invention compositions and methodsproviding for the oral absorption of peptide drug substances (aa_(n))and other poorly orally absorbed drugs are disclosed. Furthermore, ithas now been found that, through practice of the methods of the presentinvention, the length of the peptide drug entity (n) can be increased,particularly when the composition is administered parenterally, such asby intravenous (i.v.) administration, with the result of significantlyimproved pharmacological and therapeutic effects for the active drugmoiety. Accordingly, through the practice of the present invention, itis possible to chemically modify a peptide species a pseudo-peptide orpeptide mimic of known therapeutic utility to both permit the oraladministration of the species and to drastically improve itspharmacological properties even when administered through a parenteralroute. The invention also makes it possible to provide a cellular immuneresponse in immunizing against agents such as viruses for whichantibodies have been shown to enhance infectivity and in providing sucha response against both chronic and latent viral infections and againstmalignant cells.

[0006] In the present disclosure, the word “peptide” corresponds to anysequence of naturally occurring amino acids, as well as topseudo-peptides and to peptide mimics. By “pseudo-peptide,” is meant achemical modification of one or more of the amino acid residuesconstituting the peptide or of their bonds such as, but not limited to,use of amino acids in their D-configuration, use of N-methyl aminoacids, replacement of one or more peptidic bonds (—CO—NH) by a reducedbond (—CH₂NH) and/or by —NHCO, —CH₂CH₂, —COCH₂, —CHOHCH₂ or —CH2O. By“peptide mimic,” is meant any amino acid sequence in which the—C—backbone has been replaced by an oligourea backbone or anoligocarbamate backbone. ω-Peptides are also included in thisdefinition.

[0007] By “lipopeptides” is meant a combination of natural peptides (notinvolving any modified amino acids or modified bonds) and a lipidmoiety;

[0008] By “lipopseudo-peptides” is meant pseudo-peptides coupled with alipid moiety.

[0009] By “chemically modified amino acid aa_(n)“ is meant an amino acidsequence wherein at least one of the amino acid residues in their bondsis modified as set forth above in these definitions.

SUMMARY OF THE INVENTION

[0010] The instant invention is directed to pharmaceutical agents havingthe formula

Carrier-Linker_(x)-Peptide

[0011] Wherein X is 0 or 1, Carrier is selected from benzoyl,phenylacetyl, cinnamoyl, 3-OH-cinnamoyl, 3,4-OH-cinnamoyl,3,4-methylenedioxycinnamoyl, 3-methoxycinnamoyl,3,4-dimethoxy-cinnamoyl, 3,4,5-trimethoxycinnamoyl, t-butoxycarbonyl,benzoyloxycarbonyl, pivaloyl, N9-fluorenyl methoxycarbonyl, fumaroyl andderivatives thereof; Peptide is a therapeutically active peptide speciesaa_(n) wherein n is the number of amino acid residues in the peptide andis an integer of 2 to 40 and Linker is selected from C6 to C16 lipidicchains and derivatives thereof, 8-amino-3,6-dioxaoctanoic acid andpolymeric derivatives thereof, pseudopeptides and peptide mimics. Theinvention is further directed to pharmaceutical compositions containingthe afore-identified pharmaceutical agents as active ingredients and tomethods of making and using the same.

[0012] In an embodiment of the invention, Carrier or Carrier-Linker isbound to a free NH2 function of the peptide and preferably to the NH2function of the N-terminal amino acid of the peptide;

[0013] Carrier is selected from a group consisting of Cinnamoyl,3-OH-Cinnamoyl, 3,4-OH-Cinnamoyl, 3,4-methylenedioxycinnamoyl,3-methoxycinnamoyl, 3-4-dimethoxycinnamoyl, 3,4,5-trimethoxy-cinnamoyland derivatives thereof, and Peptide is a therapeutically active peptidespecies and is in the form aa_(n), where n is the number of amino acidresidues in the peptide and wherein n is an integer from 2 to 40.

[0014] In an embodiment, the present invention provides a pharmaceuticalagent comprising a carrier moiety and a therapeutically active peptidespecies, wherein the peptide is in the form aa_(n), where n is thenumber of amino acid residues in the peptide. Preferably, the carriermoiety comprises an aryl or alkyl group of sufficient length or stericbulk to protect the active peptide species from enzymatic degradation invivo. More preferably, the carrier is selected from a group comprisingcinnamoyl, benzoyl, phenylacetyl, 3-OH-cinnamoyl, 3,4-OH-cinnamoyl,3,4-methylenedioxycinnamoyl, 3-methoxycinnamoyl, 3,4-dimethoxycinnamoyl,3,4,5-trimethoxy-cinnamoyl, t-butoxycarbonyl, benzyloxycarbonyl,pivaloyl, N-9-fluorenylmethoxycarbonyl, and fumaroyl. Furthermore thecarrier moiety can be chemically linked to a therapeutically activepeptide species of the general formula aa_(n), where n is an integerfrom 2 to 40. In addition, this embodiment of the present inventioncontemplates a therapeutically active peptide species that is poorlyabsorbed orally. Preferably, n is an integer from 3 to 6. Morepreferably, n is 5. More preferably still, the therapeutically activepeptide species comprises Tyr-Gly-Gly-Phe-Met (SEQ ID NO: 1).

[0015] In an alternative embodiment, the pharmaceutical agent of thepresent invention further comprises a linker species linking the peptideto the carrier moiety. Preferably, the linker species is selected fromthe group consisting of a natural peptide, a pseudo-peptide, and apeptide mimic, each member of the group comprising 4 or fewer amino acidresidues. In one aspect of this embodiment of the present invention, thelinker species is directly bound to the carrier. Alternatively, thelinker species is bound to the carrier through a —C₆ or —C₈ acidicmoiety. More preferably, the linker species is Gly-carba-Gly, apseudo-peptide. As used herein Gly-carba-Gly represents a dipseudo-peptide constructed with two glycines, i.e., G ψ (CH₂—CH₂) G. G₉₅ψ (CH₂ —CH₂) G₉₆ represents a pseudo-peptide link between two glycinesin positions 95 and 96 of the nef peptide. More preferably still, thelinker species is associated with a —C_(n) chain, where n is an integerfrom 6 to 8. The linker species is bound to a free NH₂ function of thepeptide, preferably to the N-terminal amino acid of the peptide.

[0016] Preferably, the therapeutically active peptide species comprisesTyr-Gly-Gly-Phe-Met.

[0017] In an alternative embodiment, the pharmaceutical agent of thepresent invention further comprises a linker species linking the peptideto the carrier moiety wherein the linker species is selected from agroup comprising a C6 to C16 lipidic chain and derivatives thereof,8-amino-3,6-dioxaoctanoic acid and polymeric derivatives thereof, apseudo-peptide or a peptide mimic of less than 4 residues and anycombination thereof.

[0018] In yet another embodiment, the present invention contemplates amethod for the treatment of a physiological condition throughadministration of a therapeutically effective species comprising thesteps of chemically linking a therapeutic peptide of the general formulaaa_(n), where aa is an amino acid, and where n is an integer from 2 to40, to an alkyl or aryl carrier moiety to form a pro-drug, andadministering the pro-drug to a patient exhibiting the physiologicalcondition. Preferably, the therapeutic peptide used in the practice ofthe invention is poorly absorbed orally, and the carrier moiety isselected from the group comprising cinnamoyl, benzoyl, phenylacetyl,3-OH-cinnamoyl, 3,4-OH-cinnamoyl, 3-methoxy-cinnamoyl,3,4-methylenedioxycinnamoyl, 3,4,5-trimethoxycinnamoyl,t-butoxycarbonyl, benzyloxycarbonyl, pivaloyl,N-9-fluorenylmethoxy-carbonyl, and fumaroyl.

[0019] Alternatively, this embodiment of the present invention providesa method wherein the pro-drug is administered orally or parenterally. Inyet another alternative of the present embodiment, the methodcontemplates the use of a therapeutic peptide that is chemically linkedto the carrier moiety through a linker species.

[0020] In still another alternative embodiment, the present inventionprovides a method to enhance the absorption and bioavailability of anactive peptide drug substance of the form aa_(n), in a pharmaceuticalformulation, the method comprising the steps of adding a peptide moietyX_(n), where n=1 −3, and where a terminal amino acid is selected fromthe group consisting of Pro, Met and Arg, to one end of the peptide drugsubstance, and adding a protecting moiety to the opposite end of thepeptide drug substance.

[0021] Alternatively, the invention of the instant application providesa method to enhance the absorption and bioavailability of an activepeptide drug substance of the form aa_(n) in a pharmaceuticalformulation, the method comprising the step of formulating the activepeptide drug substance with a terminal amino acid selected from thegroup consisting of Pro, Met and Arg, and with a protective moiety onthe opposite terminus of the peptide substance, wherein the terminalamino acid (Pro, Met or Arg) is not blocked by the protective moiety.

[0022] In one embodiment, the present invention provides apharmaceutical composition for use in the treatment of physiologicalconditions comprising a carrier moiety and a therapeutically activepeptide species as defined above. The carrier comprises an aryl or alkylgroup of sufficient length and/or steric bulk to inhibit rapid enzymaticdegradation of the active drug species in vivo. A preferred carrier isselected from a group comprising cinnamoyl, benzoyl, phenylacetyl,3,4-methylenedioxycinnamoyl, 3,4,5-trimethoxy-cinnamoyl,t-butoxycarbonyl, benzyloxycarbonyl, pivaloyl,N-9-fluorenylmethoxycarbonyl, and fumaroyl. The carrier moiety ischemically linked to a therapeutic peptide of the general formulaaa_(n), where aa is an amino acid, or a chemical or structural variationthereof as defined above, where n is an integer from 2 to 40, andwherein the peptide is poorly absorbed orally. Preferably, in the drugcomposition of the invention, n is an integer from 3 to 6. Morepreferably, n is 5. In a particularly preferred embodiment, the peptideis Tyr-Gly-Gly-Phe-Met (SEQ ID NO: 1).¹

[0023] In another embodiment, the present invention provides apharmaceutical composition for administration to a patient in needthereof comprising the pharmaceutical agent described immediately above,and one or more pharmaceutically acceptable adjuvants. Preferably, thecomposition is formulated for oral administration. Alternatively, thecomposition is formulated for parenteral or topical administration. Thecomposition is advantageously formulated for intravenous administration.This embodiment of the present invention also contemplates a compositionthat releases a biologically active form of the pharmaceutical agentinto the patient's system at physiologically effective levels over aperiod of time of up to twelve hours. Most preferably, the compositionreleases a biologically active form of the pharmaceutical agent into thepatient's system at physiologically effective levels over a period oftime of up to twenty-four hours. In this embodiment of the presentinvention, the peptide species is preferably an epitope or an immunesequence characteristic of an infectious, viral or cancerous disease.

[0024] When delivered orally, the drug composition of the presentinvention is capable of delivering a systemic dose of the active drugspecies to a patient ingesting the pro-drug. The active peptide,normally immediately degraded in the gastrointestinal tract tonon-therapeutic forms, survives due to the protective effect of thecarrier component, and persists in the patient's system for prolongedperiods of time. Over time, the multi-component system is slowly brokendown, probably by enzymatic hydrolysis in the liver or the plasma,releasing the pharmacologically active component. An added benefit ofthe present invention is that the kinetics of such breakdown to releasethe active component are significantly slower than for the processesassociated with metabolic breakdown of the unmodified peptide drugspecies, effectively permitting a sustained, controlled release of theactive species into the patient's system, thus maintainingpharmacologically effective blood serum levels over an extended periodof time.

[0025] In another embodiment, the present invention contemplates apharmaceutical composition comprising a similar multi-component entitywhich, when administered through a parenteral route, makes use ofprotective activity towards the enzymatic breakdown provided byassociation of the active drug species with the carrier and/or linkingcomponents, increasing thereby the in vivo half-life of the therapeuticcomponent and improving its pharmacological properties. A preferredtherapeutic moiety for use in this embodiment of the present inventionis an epitope or an immune sequence characteristic of an infectious,viral or cancerous disease. This invention, therefore, provides adelivery method for such immune competent peptides that enhances theirpharmacological efficacy.

[0026] As would be recognized by one of skill in the art, one or more ofthe amino acids of the therapeutically active peptides used inconjunction with the present invention may be modified chemically orconformationally without significantly diminishing, and preferablyenhancing, the pharmacological activity of the therapeutic entity. Thesemodified peptides may be used in the practice of the present invention.

[0027] Ideally, the composition of the present invention is formulatedinto a pharmaceutical composition with pharmaceutically acceptableadjuvants known to those of skill in the art of pharmaceuticalformulation chemistry.

[0028] Known therapeutically active peptide species that have beendemonstrated to be pharmacologically ineffective when delivered throughtypical oral routes of administration can be modified through linkage toa carrier species to achieve effective bioavailability of the activeentity, as well as therapeutically effective controlled release of theactive species.

[0029] By, utilizing the present invention, it is now possible to treatphysiological conditions through oral administration of therapeuticallyactive peptides that would normally have to be administered throughconsiderably less desirable routes of administra-tion or with lesseffectiveness.

EXAMPLES

[0030] Met-Enkephalin (Tyr-Gly-Gly-Phe-Met*) hereinafter (YGGFM) is anaturally occurring pentapeptide (n=5) belonging to the endorphin class.It is known to be involved in the basic mechanisms of analgesia. Itproduces a transient analgesic effect when administered parenterally,but no effect has been observed when given orally. Its mechanism ofaction is believed to involve binding to opioid delta receptors in thebrain. Met-Enkephalin is very rapidly degraded in vivo into atetra-peptide that is subsequently metabolized. As for thepharmacokinetics of Met-Enkephalin, the plasma levels of the pro-drug,as well of those of the metabolites, are barely measurable, even whenadministered parenterally.

Example 1

[0031] Analgesic Effects from Administration of CY5M, aCinnamoyl-Met-Enkephalin Pro-Drug of the Present Invention.

[0032] According to the present invention, a pro-drug, designated CY5Mfor convenience of reference, comprising cinnamoyl-Met-Enkephalin(cinnamoyl-YGGFM), having the general forming carrier-aa₅, demonstratedan unexpectedly strong, long-lasting analgesia in a hot plate test withrats both when administered orally, and when administered parenterally.

[0033] Methods and Materials

[0034] Analgesic activity is classically demonstrated using a hot platetest using rats as test animals. The time to first licking of theposterior foot by the rat is recorded after the rat has been place on ahot plate maintained at an elevated temperature (40° C). This procedureprovides accurate data on central analgesic activities induced byvarious candidate drugs. Under placebo conditions, the time to firstlicking of the posterior foot of the test animal varies between 30 and50 seconds. A marked analgesia is demonstrated when this time is morethan doubled. In the experiments reported herein, a standard hot platetest was used to assess analgesia and the time to first licking of thetest animal's posterior foot was used as the triggering event formeasurement of elapsed time as indicative of the pharmacological effectof the administered drug species.

[0035] Seven groups of five male Wistar rats each were randomly assignedto the following treatments: placebo, 1 mg/kg morphine (i.v.), 10 mg/kgmorphine (oral), 10 mg/kg codeine (oral), 10 mg/kg ibuprofen (oral), 2.5mg/kg CY5M (iv.), and 2.5 mg/kg CY5M (oral). The method waspre-validated with two oral and i.v. administrations of saline placeboand the results were similar to those obtained with placebo in theexperiment reported below.

[0036] Results TABLE 1 Time to first signal activity after oraladministration Placebo 53.2 30.6 38.4 45.0 46.6 42.0 Morphine 51.8 84.881.2 58.8 48.8 42.0 Codeine 53.2 51.4 64.6 57.6 56.2 46.4 Ibuprofen 53.255.0 70.4 66.0 54.0 44.2 CY5M 53.6 46.2 78.8 78.2 82.6 98.8

[0037] TABLE 2 Time to first signal activity after i.v. administrationTime 0 h 1 h 2 h 4 h 6 h 24 h Placebo 53.2 30.6 38.4 45.0 46.6 42.0morphine 51.8 118.8 86.6 63.2 45.6 40.0 CY5M 51.0 57.0 114.0 88.2 106.086.6

[0038] In a preliminary study (data not shown), Met-Enkephalin alone wasunable to demonstrate any effect after oral administration at a 5 mg/kgdose, whereas a transient effect of about 15 minutes was observed afteri.v. administration.

[0039] If the area under the dose response curve is taken as a roughestimate of the average effect, the results indicate that 1 mg/kgmorphine i.v. is comparable to 10 mg/kg morphine oral. In comparison,CY5M, administered either orally or by i.v., is at least 8 times moreeffective than morphine using the same route of administration. Offurther interest, the above data also indicate that in no case didmorphine exhibit an analgesic effect lasting longer than six hours,whereas both oral and i.v. administrations of CY5M demonstrated asignificant analgesic effect for a period of time of 24 hours or longer.

[0040] These results indicate that using a carrier such as disclosedherein in association with a peptide drug species, permits the effectiveoral absorption of peptides of at least 5 amino acids in length andallows a much stronger pharmacological effect, with significantlyenhanced pharmacokinetic profiles, by both oral and i.v. routes ofadministration. Analogs of CY5M comprising a linker species in additionto the cinnamoyl carrier species, will demonstrate similar or greatereffects than those provided above.

Example 2

[0041] A series of carrier-linker-peptides having the formulaCarrier-(Linker)-Peptide was tested in their ability to induce T cellproliferation in a skin immunization model.

[0042] Model:

[0043] 9 week old mice were immunized by application on bare skin of 100μg of Nef(₆₆₋₉₇) peptide sequence and modifications thereof in additionto 5 μg of choleric toxin and 100 μg of oligodeoxynucleotide containinga CpG moiety (Immunology, 2002 104:1-14). 2 weeks later splenocytes werecollected and grown over 4 days in the presence of 4 differentconcentrations of Nef(₆₆₋₉₇) peptide. The proliferation was measured byincorporating tritiated thymidine.

[0044] Formulations

Nef=Nef(₆₆₋₉₇): VGFPVTPQVPLRPMTYKAAVDLSHFLKEKGGL

Lipo=Nef(₆₆₋₉₇)-palmitoyl lysilamide

CO=Cinnamoyl-Nef(₆₆₋₉₇) G₉₅ψ(CH₂—CH₂) G₉₆

CC5 =Cinnamoyl-aminovaleryl-Nef(₆₆₋₉₇) G₉₅ψ(CH₂—CH₂) G₉₆

CC8 =Cinnamoyl-aminooctanoyl-Nef(₆₆₋₉₇) G₉₅ψ(CH₂—CH₂) G₉₆

Pivgal=D-Gal(OPiv)₄-hydroxyvaleryl-aminooctanoyl-Nef(₆₆₋₉₇)

G₉₅ψ(CH₂—CH₂) G₉₆

[0045] where G₉₅ψ(CH₂—CH₂) G₉₆ represents the pseudo-peptide chemicalmodification of G₉₅-G₉₆ of the Nef(₆₆₋₉₇) sequence.

[0046] Results: Proliferation Index Conc. of Nef peptide: Nef Lipo C0CC5 CC8 Pivgal 50 10 07 12 20 16 10 5 13 08 14 21 20 08 0.5 10 06 12 2222 05 .05 03 03 08 11 10 02

[0047] The results clearly show that CC5 and CC8 have the bestproliferation index. The addition to the Cinnamoyl carrier of acovalently bound linker (Cinnamoyl+fatty acid in C5 or C8) is requiredto enhance the activity compared to the baseline. Peptides without thecarrier of the present invention=peptide+C16 fatty acid (hexadecanoicacid derivative) are not as effective. Derivatives using Pivaloylcarrier did not demonstrate improved activity. Cinnamoyl alone showed atrend to improved activity.

[0048] The results reported above clearly demonstrate that in certaincircumstances the use of an additional linker may be critical anddepends upon the peptide sequence (Nef(₆₆₋₉₇) compared to YGGFM) and thetherapeutic effect: (pharmacologically active peptide (YGGFM) comparedto immune competent peptide (Nef(₆₆₋₉₇).

[0049] The pro-drugs of the present invention are formulated intopharmaceutical compositions that contain an efficacious amount of atleast one lipopseudo-peptide in combination with an inert pharmaceuticalvehicle.

[0050] The pharmaceutical compositions contain the derivatives alone orin combination with other medications.

[0051] The pharmaceutical compositions of the invention can beadministered in different forms and by different routes, namely nasal,rectal and oral and by injection.

[0052] In the case of administration by the oral route, they may be usedin the form of tablets, pills, lozenges, gelatin capsules and evenliposomes. These compositions advantageously contain from .05 μg to 100mg of lipo-pseudo peptide, per dosage unit.

[0053] The pseudo-peptides of the invention are particularly useful inimproving the immune response against agents such as viruses for whichantibodies have been shown to enhance infectivity, particularly toprovide such a response against Goth chronic and latent viral infectiousand malignant cells.

[0054] The present invention also provides a method for enhancing theoral availability of therapeutic pseudo-peptides of the formula aa_(n),where aa is a chemically modified amino acid, or a chemical orstructural variation thereof, where n is an integer of from 2 to 40, andwherein the pseudo-peptide is poorly absorbed orally, wherein the methodcomprises the step of chemically linking the pseudo-peptide to a carriermoiety selected from the group including cinnamoyl, benzoyl,phenylacetyl, 3-OH-cinnamoyl, 3,4-OH-cinnamoyl,3,4-methylenedioxycinnamoyl, 3-methoxycinnamoyl, 3,4-dimethoxycinnamoyl,and 3,4,5-trimethoxycinnamoyl to form a pro-drug. Preferably, thisembodiment of the present invention provides a pro-drug where thepseudo-peptide is chemically linked to the carrier moiety through anon-therapeutic linker species. More preferably, the linker species isan amino acid.

[0055] The instant invention also encompasses a method for the treatmentof a physiological condition through the oral administration of atherapeutically effective species comprising the steps of chemicallylinking a therapeutic pseudo-peptide of the formula aa_(n), where aa isa chemically modified amino acid, or a chemical or structural variationthereof, where n is an integer from 2 to 40, and wherein thepseudo-peptide is poorly absorbed orally, to a carrier moiety selectedfrom the group including cinnamoyl, benzoyl, phenylacetyl,3-OH-cinnamoyl,3,4-OH-cinnamoyl,3,4-methylene-dioxycinnamoyl3-methoxycinnamoyl,3,4-dimethoxycinnamoyl and 3,4,5-trimethoxycinnamoyl to form a pro-drug,and orally administering the pro-drug to a patient exhibiting thephysiological condition. Preferably, in the practice of the method ofthe present invention, the peptide is chemically linked to the carriermoiety through a non-therapeutic linker species. More preferably still,the linker species is an amino acid.

[0056] Thus, utilizing the present invention, it is possible to treatphysiological conditions through oral administration of therapeuticallyactive pseudo-peptides that would normally have to be administeredthrough considerably less desirable routes of administration, such as byinjection.

[0057] In still another embodiment, the invention of the instantapplication provides for a method for the controlled releaseadministration of a therapeutically effective pseudo-peptide of theformula aa_(n), where aa is a chemically modified amino acid, or achemical or structural variation thereof, where n is an integer from 2to 40, and wherein the pseudo-peptide is poorly absorbed orally,comprising the steps of chemically linking the peptide to a carriermoiety selected from the group comprising cinnamoyl, benzoyl,phenylacetyl, 3-OH-cinnamoyl, 3,4-OH-cinnamoyl, 3-methoxy-cinnamoyl,3,4-dimethoxycinnamoyl, 3,4-methylenedioxycinnamoyl and3,4,5-trimethoxycinnamoyl to form a pro-drug, and orally administeringthe pro-drug to a patient. In a preferred embodiment, the pseudo-peptideis chemically linked to the carrier moiety through a non-therapeuticlinker species, and, more preferably still, the linker species is anamino acid. Due to the kinetics of the hepatic degradation of thepro-drug of the present invention, the therapeutically active peptidespecies is released to the patient's system over relatively long periodsof time, dosage dependent, to a maximum of nearly twenty-four hours.

1 1 1 5 PRT Homo sapiens 1 Tyr Gly Gly Phe Met 1 5

What is claimed is:
 1. A pharmaceutical agent having the formulaCarrier-Linker-Peptide wherein Peptide is a peptide having the formulaaa_(n) where n is an integer ≦40, Carrier is a member selected from thegroup consisting of cinnamoyl, benzoyl, phenylacetyl, 3-OH-cinnamoyl,3,4-OH-cinnamoyl, 3,4-methylenedioxycinnamoyl, 3-methoxycinnamoyl,3,4-dimethoxycinnamoyl, 3,4,5-trimethoxy-cinnamoyl, t-butoxy-carbonyl,benzyloxycarbonyl, pivaloyl, N-9-fluorenylethoxycarbonyl, fumaroyl andderivatives thereof and Linker is a member selected from the groupconsisting of C6 to C16 lipidic chains and derivatives thereof,8-amino-3,6-dioxaoctanoic acid and polymeric derivatives thereof,natural peptides, pseudopeptides of less than 4 residues, peptide mimicsof less than 4 residues and combinations thereof.
 2. The pharmaceuticalagent of claim 1 wherein Linker is a member selected from the groupconsisting of natural peptides, pseudo peptides of less than 4 residuesand peptide mimics of less than 4 residues.
 3. The pharmaceutical agentof claim 1, wherein n is an integer of from 3 to
 6. 4. Thepharmaceutical agent of claim 1, wherein n is
 5. 5. The pharmaceuticalagent of claim 1, wherein Peptide is Tyr-Gly-Gly-Phe-Met.
 6. Thepharmaceutical agent of claim 1 wherein Carrier is a member selectedfrom the group consisting of cinnamoyl, 3-OH-cinnamoyl,3,4-OH-cinnamoyl, 3-methoxycinnamoyl, 3,4-dimethoxycinnamoyl, and3,4,5-trimethoxy-cinnamoyl.
 7. The pharmaceutical agent of claim 1wherein Carrier is cinnamoyl.
 8. The pharmaceutical agent of claim 1wherein Linker is a -C6 or C8 acidic moiety.
 9. The pharmaceutical agentof claim 1 wherein Linker is Gψ (CH₂-CH₂) G.
 10. The pharmaceuticalagent of claim 1 wherein Peptide is an epitope or an immune sequencecharacteristic of an infectious, viral or cancerous disease.
 11. Apharmaceutical composition for administration to a patient in needthereof comprising a pharmaceutical agent according to claim 1 and oneor more pharmaceutically acceptable adjuvants.
 12. The pharmaceuticalcomposition of claim 11 wherein the composition is formulated for oraladministration.
 13. The pharmaceutical composition of claim 11 whereinthe composition is formulated for parenteral administration.
 14. Thepharmaceutical composition of claim 11 wherein the composition isformulated for intravenous administration.
 15. The pharmaceuticalcomposition of claim 11 wherein the composition releases a biologicallyactive form of the pharmaceutical agent into the patent's system atphysiologically effective levels over a period of time of up to twelvehours.
 16. The pharmaceutical composition of claim 11 wherein thecomposition releases a biologically active form of the pharmaceuticalagent into the patient's system at physiologically effective levels overa period of time of up to twenty-four hours.
 17. The pharmaceuticalcomposition according to claim 11 wherein Peptide is an epitope or animmune sequence characteristic of an infectious, viral or cancerousdisease.
 18. A method for treatment of a physiological condition throughadministration of a peptide species comprising the steps of chemicallylinking a peptide of the general formula aa_(n), where aa is an aminoacid, and where n is an integer ≦40, to an alkyl or aryl carrier moietyto form a pro-drug, and administering the pro-drug to a patientexhibiting the physiological condition.
 19. The method of claim 18wherein the peptide is poorly absorbed orally.
 20. A method for thetreatment of a physiological condition which comprises administering apharmaceutical agent according to claim 1 to a patient exhibiting thephysiological condition.
 21. The method according to claim 20 whereinthe pharmaceutical agent is administered orally or parenterally.
 22. Amethod for the treatment of a physiological condition which comprisesadministering a pharmaceutical agent having the formulaCarrier-Linker_(x)-Peptide wherein X is 0 or 1, Peptide is a peptidehaving the formula aa_(n), wherein n is an integer ≦40, Carrier is amember selected from the group consisting of cinnamoyl, benzoyl,phenylacetyl, 3-OH-cinnamoyl, 3,4-methylene-dioxycinnamoyl,3-methoxycinnamoyl, 3,4-dimethoxycinnamoyl, 3,4,5-trimethoxy-cinnamoyl,t-butoxycarbonyl, benzyloxycarbonyl, pivaloyl,N-9-fluorenylmethoxycarbonyl, fumaroyl and derivatives thereof andLinker is a member selected from the group consisting of C6 to C16lipidic chains and derivatives thereof, 8-amino-3,6-dioxaoctanoic acidand polymeric derivatives thereof, natural peptides, pseudopeptides ofless than 4 residues, peptide mimics of less than 4 residues andcombinations thereof.
 23. The method for the treatment of aphysiological condition according to claim 22 which comprisesadministering a pharmaceutical agent wherein x is 0 and Carrier-Peptideis a pro-drug.
 24. The method for the treatment of a physiologicalcondition according to claim 22 which comprises administering apharmaceutical composition wherein x is 1 and Carrier-Linker-Peptide isa pro-drug.